GLEDJAN CAKA, LEDIA VASJARI, INA GJYMENGA
Abstract
Melanoma is the most aggressive form of skin cancer, characterized by rapid metastasis, early dissemination, and high resistance to systemic therapies. Although it represents less than 5% of all skin cancer cases, it accounts for the majority of skin cancer–related deaths. Its development is driven by complex interactions between environmental factors, particularly ultraviolet radiation, and genetic alterations affecting key oncogenes and tumor suppressor genes such as BRAF, NRAS, KIT, PTEN, and CDKN2A. Among these, the BRAF V600E mutation is the most prevalent, leading to constitutive activation of the MAPK/ERK signaling pathway and promoting melanoma progression. While targeted therapies such as BRAF inhibitors have improved patient outcomes, acquired resistance frequently emerges, highlighting the need for effective combination treatment strategies.This study evaluates the therapeutic potential of drug combinations in three melanoma cell lines—LOX-IMVI, SK-MEL-28, and M14—using predictive modeling and synergy quantification methods (LOEWE, BLISS, ZIP, and HSA) implemented through SynergyFinder. The combination of vemurafenib and dacarbazine demonstrated a synergistic effect in LOX-IMVI cells according to the ZIP model, while consistently showing additive effects across other models. SK-MEL-28 cells exhibited predominantly additive responses, reflecting their distinct molecular profile with BRAF V600E mutation and wild-type NRAS. The M14 cell line displayed response patterns similar to LOX-IMVI, likely due to shared BRAF V600E mutations. Although strong synergy was limited, the reproducible additive effects observed across cell lines suggest clinically relevant benefits, supporting combination therapy as
a promising approach to enhance efficacy and reduce toxicity in melanoma treatment.
Key words: Melanoma, Drug, Toxicity, Cell line, Synergy.